Background: Drug resistance is one of the biggest challenges in cancer therapy. temozolomide (TMZ) represents the most important chemotherapeutic option for glioma treatment. However, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioma, and the underlying mechanisms were not fully addressed. Herein, we demonstrate that the elevated expression of CD147 contributes to TMZ resistance in glioma cells, potentially through the post-translational regulation of Nrf2 expression./nMethods: Cell-based assays of CD147 triggered drug resistance were performed through Edu-incorporation assay, CCK8 assay, TUNEL staining assay and flow cytometric assay. Luciferase reporter assay, protein stability related assays, co-immunoprecipitation assay were used to determine CD147 induction of Nrf2 expression through β-TrCP dependent ubiquitin system. Finally, the effect of the CD147/Nrf2 signaling on glioma progression and TMZ resistance were evaluated by functional experiments and clinical samples./nResults: Based on the analysis of clinical glioma tissues, CD147 is highly expressed in glioma tissues and positively associated with tumor malignancy. Suppression of CD147 expression increased the inhibitory effect of TMZ on cell survival in both U251 and T98G cells, whereas the gain of CD147 function blocked TMZ-induced ROS production and cell death. Mechanistic study indicates that CD147 inhibited GSK3β/β-TrCP-dependent Nrf2 degradation by promoting Akt activation, and subsequently increased Nrf2-mediated anti-oxidant gene expressions. Supporting the biological significance, the reciprocal relationship between CD147 and Nrf2 was observed in glioma tissues, and associated with patient outcome./nConclusions: Our data provide the first evidence that glioma resistance to TMZ is potentially due to the activation of CD147/Nrf2 axis. CD147 promotes Nrf2 stability through the suppression of GSK3β/β-TrCP dependent Nrf2 protein degradation, which results in the ablation of TMZ induced ROS production. As such, we point out that targeting CD147/Nrf2 axis may provide a new strategy for the treatment of TMZ resistant gliomas.

中文翻译：

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CD147通过调节β-TrCP/Nrf2通路赋予胶质瘤细胞对替莫唑胺的耐药性

背景：耐药性是癌症治疗中最大的挑战之一。替莫唑胺（TMZ）是胶质瘤治疗最重要的化疗选择。然而，由于 TMZ 在胶质瘤中的常见耐药性，其治疗效果仍然非常有限，并且其潜在机制尚未完全解决。在这里，我们证明了 CD147 的表达升高有助于胶质瘤细胞中的 TMZ 抗性，可能是通过 Nrf2 表达的翻译后调节。/n方法：通过 Edu 掺入试验、CCK8 试验、TUNEL 染色试验和流式细胞仪试验进行基于细胞的 CD147 引发的耐药性试验。荧光素酶报告基因测定、蛋白质稳定性相关测定、免疫共沉淀测定用于确定 CD147 通过 β-TrCP 依赖性泛素系统诱导 Nrf2 表达。最后，通过功能实验和临床样本评估了 CD147/Nrf2 信号传导对胶质瘤进展和 TMZ 耐药性的影响。/n结果：基于临床胶质瘤组织分析，CD147在胶质瘤组织中高表达，与肿瘤恶性程度呈正相关。CD147 表达的抑制增加了 TMZ 对 U251 和 T98G 细胞中细胞存活的抑制作用，而 CD147 功能的获得阻止了 TMZ 诱导的 ROS 产生和细胞死亡。机制研究表明，CD147 通过促进 Akt 激活抑制 GSK3β/β-TrCP 依赖性 Nrf2 降解，并随后增加 Nrf2 介导的抗氧化基因表达。支持生物学意义，在胶质瘤组织中观察到 CD147 和 Nrf2 之间的相互关系，并与患者预后相关。/n结论：我们的数据提供了第一个证据表明胶质瘤对 TMZ 的耐药性可能是由于 CD147/Nrf2 轴的激活。CD147 通过抑制 GSK3β/β-TrCP 依赖的 Nrf2 蛋白降解来促进 Nrf2 的稳定性，从而消除 TMZ 诱导的 ROS 产生。因此，我们指出靶向 CD147/Nrf2 轴可能为治疗 TMZ 耐药胶质瘤提供新的策略。